Assoziation von HNSCC-assoziierten Markern mit klinisch-pathologischen Merkmalen - eine immunhistochemische Analyse

Die Inzidenz von Plattenepithelkarzinomen des Kopf-Halsbereiches (head and neck squamous cell carcinomas, HNSCC) betrug im Jahre 2018 weltweit ca. 830.000 Fälle (ohne Hautkarzinome), wobei die Mortalität im gleichen Zeitraum bei ca. 444.000 lag. Ursächlich für diese seit Jahren im Wesentlichen unver...

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Bibliographic Details
Main Author: Kronen, Marie
Contributors: Mandic, Robert (Prof. Dr. med.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2021
Online Access:PDF Full Text
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The worldwide incidence of head and neck squamous cell carcinomas (HNSCC) was 830.000 cases in 2018, with a mortality of 444.000 cases in the same year. Mechanisms of tumor resistance, such as the resistance to radio- and chemotherapy, are thought to cause this poor prognosis. In previous studies by our group, genetic analysis found an increased expression of the ABC (ATP-Binding Cassette) transporters ABCG2 and ABCC2 in cisplatin (CDDP) resistant HNSCC cell lines compared to cisplatin sensitive cell lines. We were able to show that the observed overexpression contributes to resistance in the CDDP resistant cell lines. In addition, the CDDP resistant cell lines also showed truncating mutations in the C-terminal region of the tumor suppressor TP53, leading to cytoplasmatic sequestration and lower protein expression (p53). Based on these findings, this retrospective study investigates the expression of ABC transporters in HNSCC patient samples by immunohistochemistry (IHC). Along with ABCC2 and ABCG2, the expression of the proliferation marker Ki-67, the stem cell marker cytokeratin 19 (CK19) and p53 were examined in HNSCC samples and controls. The immunohistochemical expression levels of these 5 marker proteins were subsequently correlated with each other and with available clinical data of the patients and checked for significant associations by contingency table analysis. The study cohort consisted of 98 patients (male: 84; female: 14). Of those, 10 HNSCC samples were obtained from the mouth, 41 from the pharynx, and 47 from the larynx. 21 samples were acquired from recurrent cases. This study found that all five markers were significantly overexpressed in HNSCC (p< 0.05), and that ABC transporter expression was independent of the expression of the other markers. There was no correlation between the expression of ABCC2, ABCG2, and p53 and the clinical data. However, the expression of the markers Ki-67 (p=0.013) and CK19 (p=0.018) were significantly higher in less differentiated tumors. Furthermore, Marker CK19 was also significantly higher expressed in patients with higher T-state (p=0.021) and lymph node metastasis (p=0.049). Combined overexpression of markers ABCC2, ABCG2, Ki-67, and CK19 points towards poor prognosis: less differentiated tumors (≥ G2, p=0.017), progressed tumor growth (≥ T2, p=0.011), as well as lymph node metastasis (N+, p=0.05). There was no statistical significance when including p53 into the analysis. Limitations of this study were the retrospective design (data from 2007 - 2011) and immunohistochemistry (IHC) being the only method used. Not all parameters could be obtained in the required quality from the available patient records. For example, data about tobacco smoking, alcohol consumption, and information about HPV infection were missing. Thus, no stratification was carried out according to HPV and no meaningful conclusions regarding these parameters could be drawn. The matching of controls and tumors in terms of age and location was insufficient. The use of non-parametric data represents a disadvantage. Score systems enable and ease evaluations and should, as in this work, consider the color intensity and percentage of positive cells. However, grouping also means that values from border areas are assigned to one or the other group, which can lead to an overestimation or underestimation of a sample. Taking the mentioned limitations into account, it can be concluded that a combined immunohistochemical staining of ABCG2, ABCC2, Ki-67 and CK19 in the early diagnosis of HNSCC can be helpful in filtering out high-risk patients with an unfavorable prognosis. However, there was no clear correlation between increased ABCC2 and ABCG2 expression and more advanced tumor stages. Additional prospective studies on larger, more homogeneous collectives in combination with genetic analysis are required to further evaluate the role of ABCG2 and ABCC2 for chemotherapy resistance in HNSCC.